The Rockefeller University Hospital, a GCRC awardee since 1963, has been the continuous "home" for clinical and translational science at Rockefeller since 1910. It has been the site of numerous landmark scientific and clinical contributions, and many of its trainees have gone on to become academic leaders. With the new resources available under a Clinical and Translational Science Award (CTSA), a core faculty of. distinguished investigators, whose research spans the basic-translational spectrum and encompasses a broad range of scientific and medical disciplines, will integrate and expand their scientific and educational programs in a new Rockefeller University Center for Clinical and Translational Science. The new Center will transform clinical and translational research by encouraging new studies, and by enhancing and centralizing the support structures required to conduct studies with scientific rigor and an absolute commitment to protection of human subjects and participant safety. The key elements in the transformation will be: 1) A new governance structure reflecting the NIH cooperative agreement (U54) "assistance" mechanism, 2) Creation of a new K-12 Clinical Research Scholars Program offering Masters and PhD level degrees to complement the current Clinical Scholars Program, 3) Infrastructure enhancements to facilitate the development and conduct of clinical protocols under the principle of Good Clinical Practice (GCP), including biomedical informatics, biostatistics. bionutrition, research nursing, research pharmacy, participant recruitment and community engagement, and regulatory support and oversight from the clinical research (research subject advocate) support office, 4) Development of innovative and novel core methodologies related to dendritic cell therapy;vaccine development for HIV, hepatitis C, and malignancies;genetics/genomics;assessing the immune response;and metabolic phenotyping. The Center will continue Rockefeller's tradition of focusing on the interface between scientific discovery, human pathophysiology, and novel diagnostic, preventive and therapeutic strategies. It will partner with industry, when mutually beneficial, to achieve these goals. The Center will also be an active member of the National CTSA Consortium, offering the Consortium novel ideas and tools for conducting and evaluating clinical and translational research. It will also eagerly adopt the best practices identified by the Consortium and adhere to the standards set by the Consortium. Methillin resistant S. aureus (MRSA) was first identified in clinical specimen in 1961 - shortly after the introduction of the first beta-lactamase resistant antibiotic - Celbenin - into clinical practice. The key component of this resistance mechanism - the mecA gene - encoding a protein with very low affinity to all beta-lactam antibiotics - is not a native gene for S. aureus but has been acquired on multiple occasions from a "foreign" source in the form of chromosomal cassettes. MRSA clones have emerged as major causative agents of serious - and often life-threatening - infections in hospitals worldwide and beginning with the late 1990s MRSA also found its way into the community. The most widely spread epidemic clones of MRSA also acquired resistance traits to the great majority of antimicrobial agents and therapeutic options against such multidrug resistant strains have become reduced to less than a handful of agents. The primary motive of this grant proposal is to find novel intervention strategies against MRSA by exploring more closely the mechanism of beta-lactam resistance. Critical clues for such novel strategies were observations made in the two collaborating laboratories. The research program will use a combination of genetic, biochemical and metabolomic approaches and will be divided into four Specific Aims. Aim 1 will use metabolomic approaches to identify the mechanisms by which a library of auxiliary mutants can reduce resistance level of an MRSA strain. Aim 2 will compare the very different resistance levels produced by subpopulations of heterogeneously resistant epidemic clones of MRSA. Aim 3 will use genome sequencing to identify determinants in the genetic background of S. aureus that control the level of resistance to oxacillin. Aim 4 will use five contemporary isolates of MRSA recovered in Yr 2011 in New York hospital